Tumor lysis syndrome following letrozole for locally advanced breast cancer: a case report

Background Letrozole, an aromatase inhibitor, is used to treat breast cancer in postmenopausal women. Tumor lysis syndrome (TLS) is a complication that can trigger multiple organ failure caused by the release of intracellular nucleic acids, phosphate, and potassium into the blood due to rapid tumor cell disintegration induced by drug therapy. TLS is uncommon in solid tumors and occurs primarily in patients receiving chemotherapy. Herein, we report a rare occurrence of TLS that developed in a patient with locally advanced breast cancer following treatment with letrozole. Case presentation An 80-year-old woman with increased bleeding from a fist-sized left-sided breast mass presented to our hospital. Histological examination led to a diagnosis of invasive ductal carcinoma of the luminal type. The patient refused chemotherapy and was administered hormonal therapy with letrozole. Seven days after letrozole initiation, she complained of anorexia and diarrhea. Blood test results revealed elevated blood urea nitrogen (BUN) and creatinine (Cr) levels, and she was admitted to our hospital for intravenous infusions. On the second day after admission, marked elevations of LDH, BUN, Cr, potassium, calcium, and uric acid levels were observed. Furthermore, metabolic acidosis and prolonged coagulation capacity were observed. We suspected TLS and discontinued letrozole, and the patient was treated with hydration, febuxostat, and maintenance hemodialysis. On the third day after admission, her respiratory status worsened because of acute respiratory distress syndrome associated with hypercytokinemia, and she was intubated. On the fourth day after admission, her general condition did not improve, and she died. Conclusions Although TLS typically occurs after chemotherapy initiation, the findings from the present case confirm that this syndrome can also occur after hormonal therapy initiation and should be treated with caution.


Background
Letrozole, an aromatase inhibitor, is used to treat breast cancer in postmenopausal women.Tumor lysis syndrome (TLS) is a complication that can cause multiple organ failure due to the release of intracellular nucleic acids, phosphate, and potassium into the blood owing to rapid tumor cell disintegration triggered by drug therapy.TLS is most commonly reported in hematologic malignancies, but can also occur in solid tumors in rare cases.The frequency of TLS in solid tumors has been reported to be less than 0.3% [1].In metastatic solid tumors, TLS occurs primarily in patients receiving chemotherapy, and only two TLS cases associated with letrozole have previously been reported [2,3].
This case report aimed to document and analyze a rare occurrence of TLS that developed in a patient with locally advanced breast cancer following treatment with letrozole, a hormone therapy.This report delves into the clinical presentation, diagnostic processes, treatment interventions, and the unfortunate fatal outcome associated with TLS in this scenario.

Case presentation
An 80-year-old female patient with no prior medical history had been treated at another hospital for bleeding from a 10-cm-sized tumor in her left breast.Breast cancer was suspected, but she refused to undergo an examination.Six months later, the tumor grew even larger, and bleeding from the breast tumor did not stop; therefore, she visited our hospital.The left breast tumor was 12 × 10 cm in size, with hemorrhage and effusion noted on her clothing (Fig. 1).Hemostasis was achieved during the examination at our hospital.Blood tests revealed mild elevation of the blood urea nitrogen (BUN)/creatinine (Cr) ratio but no anemia, and tumor markers were normal (BUN, 30.7 mg/dl; Cr, 0.94 mg/dl, LDH, 134 U/L, carcinoembryonic antigen, 3.62 ng/ml; cancer antigen 15-3, 14 U/ml).
Computed tomography revealed a 12 × 10 cm left breast mass, which was suspected to have invaded the epidermis and pectoralis major muscle.Axillary lymph nodes were not enlarged, and there was no obvious distant metastasis (Fig. 2).
Needle biopsy revealed a diagnosis of invasive ductal breast carcinoma (cT4bN0M0 cStageIIIB, estrogen receptor 50%, progesterone receptor 70%, human epidermal growth factor receptor 2 [HER2] 1 + , Ki67 26.16%), but most of the tissue was necrotic.The patient refused surgery or chemotherapy and was initiated on letrozole 2.5 mg/day.The bleeding area from the tumor was followed up with Mohs paste [4] and Rozex gel ® (Mohs paste is not covered by insurance in Japan).
One week later, the patient complained of nausea and diarrhea.Blood tests revealed marked renal dysfunction and hyperuricemia, and she was admitted to the hospital for intravenous infusions.On the second day after admission, blood tests revealed further renal function deterioration, marked metabolic acidosis, and prolonged coagulopathy (Table 1).There were no arrhythmias or clinical findings suggestive of seizures or pulmonary emboli.The left breast tumor had shrunk and the surface tumor had self-destructed due to necrosis.Therefore, TLS and associated disseminated intravascular coagulation syndrome associated with tumor shrinkage with letrozole were suspected.High-volume rehydration, rasburicase for the hyperuricemia, and hemodialysis were initiated.On the third day after admission, the acidosis did not improve, and the patient developed respiratory distress and impaired consciousness.The patient refused intubation and underwent bilevel positive airway pressure ventilation.Although hemodialysis was performed daily, the patient's general condition did not improve.Hence, we decided to perform a left mastectomy under local anesthesia in the intensive care unit (ICU) to reduce the tumor volume.The majority of the tumor was necrotic, and the tissue was fragile.There was no obvious evidence of pectoralis major muscle involvement.Four days after admission, the acidosis did not improve and liver failure progression was observed.Hemodialysis was not expected to be effective; after consultation with her family, dialysis was discontinued, and the patient died 2 h later.

Discussion
TLS is a potentially lethal oncological emergency in which massive tumor cell destruction causes severe electrolyte and metabolite abnormalities secondary to the release of intracellular components into the bloodstream, resulting in hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia.Hyperuricemia and hyperphosphatemia induce acute renal injury owing to uric acid precipitation and calcium phosphate deposition in the renal tubules.Hypocalcemia and hyperkalemia can also cause electrocardiographic abnormalities, arrhythmias, neuromuscular symptoms, and seizures.Following the introduction of the Cairo-Bishop definition, proposed in 2004, which provides TLS diagnostic criteria, TLS can now be diagnosed clinically, using laboratory values [5,6].The present patient met the Cairo-Bishop definitions of laboratory and grade II clinical TLS.After admission, the patient was treated with a high volume of rehydration fluid, glucose insulin therapy for hyperkalemia, and rasburicase for hyperuricemia.On the second day after admission, the patient developed progressive metabolic acidosis, and hemodialysis was initiated.On the third day after admission, the patient's condition worsened.At this point, we considered the presence of the tumor to be related to the worsening condition; thus, we performed an emergency mastectomy under local anesthesia in the ICU.Unfortunately, the patient did not respond to these treatments and eventually died.At this point, we considered that the presence of the tumor was associated with worsening of the condition.Therefore, although not standard of care, we performed an emergency mastectomy under local anesthesia in the ICU.Unfortunately, the patient did not respond to these treatments and ultimately died.
There were two reasons why we decided to perform surgery.The first reason was that the patient's general condition had deteriorated to the point where she developed consciousness disorders, and there was no other systemic treatment available.The second reason was that tumor removal might have been significant, considering the mechanism of tumor lysis syndrome.However, there have been no reports on the effectiveness of surgical resection of tumors in the treatment of tumor lysis syndrome, so it remains unclear whether this procedure was appropriate.
In the present case, although the patient had a solid tumor and was at a low risk for TLS, a prophylactic uric acid-lowering drug may have been indicated because of the large tumor volume and slightly elevated uric acid level (8.4 mg/dl prior to treatment).Therefore, control of elevated uric acid levels is important to prevent renal dysfunction.Furthermore, recognizing the high risk of TLS and assessing the risk factors prior to treatment are of utmost importance.In the present case, the high efficacy of letrozole was likely the trigger for TLS although the possibility of renal failure due to Mohs paste cannot be ruled out.In particular, clinical TLS reportedly increases mortality rates (83 vs. 24%; p < 0.001) [7].The development of acute kidney injury associated with TLS is a strong predictor of mortality [8].Regardless of cancer type, the mortality rate increases by 20-50% in cases of undiagnosed or delayed TLS diagnosis in solid tumors [9].The best TLS management is prevention.Omori et al. [10] previously reported that prophylactic infusion and lowering uric acid levels prevented TLS in patients with breast cancer with high tumor volumes and hyperuricemia.
TLS has also been commonly reported in hematological malignancies but is becoming more frequently noted in solid tumors as treatments become more efficient [11].Table 2 (modified from Watkinson and Hari Dass [3]) summarizes all reported TLS cases caused by breast cancer treatment.A total of 22 TLS cases associated with breast cancer have been reported, including  TLS tumor lysis syndrome three with hormone therapy only (one with tamoxifen and two with letrozole), three with hormone therapy plus a cyclin-dependent kinase 4/6 inhibitor or PIK3CA inhibitor, two with anti-HER2 therapy, nine with chemotherapy, two with radiation therapy, and three without therapy.Overall, chemotherapy, hormone therapy, molecular-targeted drug therapy, radiation therapy, and no therapy can all cause TLS.

Conclusions
Herein, we describe the third reported TLS case in a patient with locally advanced breast cancer who developed the syndrome after receiving letrozole.Oncologists treating patients with breast cancer should be extremely cautious when treating patients with a high TLS risk, even without cytotoxic chemotherapy.As TLS can cause fatal outcomes, physicians should consider the risks and determine the appropriate prophylaxis before initiating treatment.

Fig. 1
Fig. 1 Patient photograph.The image shows the left breast lesion with irregular margins as well as necrotic and pyogenic lesions

Fig. 2
Fig. 2 Breast computed tomography image.A 12 × 10-cm-sized mass was found in the left breast.No obvious pectoralis major muscle invasion was observed.Additionally, there was no significant lymph node swelling or findings suspicious of distant metastasis

Table 1
Blood work during hospitalization showing elevated uric acid, acute renal failure, electrolyte abnormalities consistent with tumor lysis syndrome Elevated uric acid, acute renal failure, and electrolyte abnormalities consistent with tumor lysis syndrome were observed

Table 2 A
Summary of previously published reports of TLS and hyperuricemia cases

Table 2
[3]ntinued)The above cases were those available in the literature during publication of this report.The table details the publication author, patient age, any tumor type and stage specifics (where reported in the publication), treatment administered, risk factors specified, and outcome.Modified from Watkinson and Hari Dass[3]